We have recently shown in preclinical studies using clinically relevant pancreatic ductal adenocarcinoma (PDAC) models that angiotensin system inhibitors (ASIs), including the angiotensin receptor blocker losartan, can enhance the delivery and efficacy of cytotoxic agents by affecting the tumor microenvironment (PNAS 2011, Nat Commun 2013). The mechanisms underlying this benefit include ?normalization? of cancer-associated fibroblasts and extracellular matrix (ECM), resulting in blood vessel decompression, improved perfusion, and decreased hypoxia. These exciting preclinical findings formed the basis of an ongoing Phase II clinical trial at Massachusetts General Hospital (MGH), which combines losartan with cytotoxic therapy ? FOLFIRINOX and then chemoradiotherapy in unresectable locally advanced PDAC (NCT01821729). An interim analysis of this trial indicates that adding losartan to neoadjuvant cytotoxic therapy doubles the frequency of conversion to resectable tumors (52%) and strikingly improves overall survival (OS) in these PDAC patients. Remarkably, transcriptomic analysis of tumor biopsies from PDAC patients further indicates that ASI treatment not only normalizes ECM-related phenotypes but also upregulates key pathways associated with anti-tumor immunity involving both adaptive (e.g., CD8+ T cells) and innate (e.g., dendritic cells (DCs)) immune components of the PDAC tumor microenvironment. Based on these preclinical and clinical findings, we hypothesize that ASIs in combination with cytotoxic agents will reprogram the heterogeneous, pro-fibrotic, and immunosuppressive PDAC tumor microenvironment to one that is immunostimulatory. We further propose that combining ASIs and cytotoxic agents will enhance the delivery and efficacy of immunotherapies, which until now have had limited or no benefit in PDAC patients. To test these hypotheses, we designed three Specific Aims: 1) Uncover how losartan combined with cytotoxic agents alters tumor microenvironmental components (ECM, blood vessels, hypoxia) and immune cells, in locally advanced PDAC patients; 2) Dissect the causal role of drug- induced adaptive and innate immune cells in the anti-tumor response in orthotopic (implanted and genetically engineered) PDAC models in mice; and 3) Evaluate whether combining ASI-induced tumor microenvironment reprogramming along with cytotoxic therapies enhances the efficacy of immune checkpoint blockers. Based on our preclinical and clinical data, our tightly integrated and multidisciplinary team of investigators, and our bench-to-bedside-and-back research approach, we anticipate that successful completion of these studies will positively impact the development of new treatments for locally advanced PDAC patients who currently have a 5-year survival rate of ~11%. Moreover, because we will actively participate in the PDAC Consortium, the knowledge gained in these studies will be available for other studies of the immune tumor microenvironment in PDAC that are undertaken within the Consortium. Through this work, we will develop innovative approaches to enhance anti-tumor immunity in this intractable disease.